JP2019515942A - Ambrisentan for use in the treatment of acute renal failure - Google Patents

Abstract

Ambrisentan and its preparation for use in the treatment and prevention of acute renal failure associated with renal vasoconstriction.

Description

Cross Reference to Related Applications Not applicable.
TECHNICAL FIELD The present invention relates to the treatment, prevention, and associated therapeutic and prophylactic formulations of acute renal failure associated with renal vasoconstriction. The invention further relates to the identification of the reduction of renal function due to vasoconstriction, and to formulations suitable for such identification.

  Acute renal failure is a life-threatening condition when the kidneys can not suddenly filter out waste products from the blood. Also known as acute renal failure or acute kidney injury, this condition can occur over several hours or days. Most commonly, it affects people who are already hospitalized, especially those who have serious illness. See, for example, the report on renal failure by Mayo Clinic (http://www.mayoclinic.org/diseases-conditions/kidney-failure/basics/definition/con 20024029).

  The various signs and symptoms of acute renal failure may be normal urine volume but decreased urine volume; fluid retention causing swelling in the legs, ankles or feet; sleepiness; shortness of breath; fatigue; confusion; Nausea; seizures or coma in severe cases; chest pain or pressure. However, some patients have no signs or symptoms, and this condition is detected in clinical tests performed for other reasons. Regardless of the specific symptoms that may be present, the mortality rate for acute renal failure is estimated to be greater than 50%.

  Acute renal failure can occur as a result of having a condition that slows blood flow to the kidney when the kidney is directly damaged or when the ureter, which is the drainage tube of the kidney, is occluded. It is also caused by conditions where renal vascular resistance is markedly increased and renal vasoconstriction leads to an increase in endothelin (ET) which causes a substantial decrease in blood flow to the kidney, followed by inadequate renal blood flow.

  Endothelin is a naturally occurring peptide found in plasma. Endothelin has two known receptors: endothelin A receptor (ETR-A) and endothelin B receptor (ETR-B). ETR-A is capable of mediating increased vascular tone and is usually found in smooth muscle tissue of blood vessels. Binding of endothelin to ETR-A results in vasoconstriction. ETR-B plays a role in mediating vascular tone as well as vasodilation. In addition, endothelin B receptors are present in the renal tubules and collecting ducts and are involved in diuresis. ETR-B also acts as a clearance receptor for endothelin.

  Types of acute renal failure associated with renal vasoconstriction caused by endothelin include, for example, hepatorenal disorder such as hepatorenal syndrome (HRS), refractory ascites and dilated hyponatremia. Other disorders associated with renal vasoconstriction caused by endothelin include, for example, delayed graft function (DGF), calcineurin inhibitor nephrotoxicity (CNI), contrast-induced acute kidney injury (CIAKI), cardiorenal syndrome (CS) And acute kidney injury (AKICS) after cardiac surgery.

  Hepatic kidney injury is a condition characterized by the presence of renal failure in a subject with liver failure (eg, cirrhosis with or without ascites, acute liver failure, etc.). Such hepatorenal disorders include HRS, refractory ascites and dilute hyponatremia. HRS is a disease with high mortality (HRS type I up to 50% in 2 weeks) and the probability of survival is very low. Hepatic kidney disease occurs in patients with advanced liver disease, generally without a history of kidney disease, and characterized by extreme renal vasoconstriction. A notable clinical feature is rapid progressive renal failure, which is refractory to conventional treatments, such as rapid infusion and / or the use of diuretics. There is no specific and effective treatment for this condition. In such cases, liver transplantation is generally considered, and restoration of liver function may correct and improve kidney function. However, it is generally difficult to assess whether renal failure is functional (ie, reversible and secondary to renal vasoconstriction induced by hepatic failure). , Liver and kidney transplantation may be performed simultaneously. If renal failure is not essentially functional, simultaneous liver and kidney transplantation are preferred. Refractory ascites and dilute hyponatremia are kidney complications observed in patients with advanced liver disease secondary to intense sodium and water reabsorption by the kidney, characterized by intense vasoconstriction of the kidney. The main clinical features of refractory ascites are the inability to use a diuretic in the treatment of recurrent ascites, or the reduced efficacy of the diuretic, and frequent punctures are required. Dilutable hyponatremia is a metabolic disorder characterized by high water retention and dilution and low serum sodium levels.

  Delayed graft function (DGF) is a complication of kidney transplantation and is a transplanted kidney derived from a dead or expanded donor (eg, an older donor, a donor with hypertension or a donor with high end serum creatinine) Occur most frequently in DGF is rare in survival donor kidney transplantation. DGF can complicate the postoperative course in 20 to 40% of cases, and there is no treatment for this condition. Clinically, DGF appears as poorly functional or nonfunctional kidney after transplantation. It is characterized by higher endothelin levels, lower glomerular filtration rate and increased renal vascular resistance.

  Contrast agent-induced acute kidney injury (CIAKI), also known as Contrast-Induced Nephropathy, is treated with subjects who have a history of renal failure, elderly subjects, or large amounts of contrast agent It is a renal complication after administration of the iodine type radiocontrast agent which occurs most frequently in the subject. CIAKI is characterized by an increase in renal vascular resistance and a decrease in glomerular filtration rate, the latter being reflected as an increase in serum creatinine.

  Cardiorenal syndrome (CS) is a common kidney complication that occurs in patients with heart failure and is characterized clinically by retention of water and sodium and decreased glomerular filtration rate. Some forms of CS are characterized by increased renal vascular resistance, decreased renal blood flow, decreased urinary sodium and sodium excretion, and respond poorly to diuretic therapy.

  Acute Renal Injury After Cardiac Surgery (AKICS) is a complication that occurs in the immediate post-operative period of subjects undergoing complex cardiac surgery. It is characterized by increased renal vascular resistance, decreased renal blood flow, and decreased glomerular filtration rate.

  Calcineurin inhibitor nephrotoxicity (CNI) exhibits acute or chronic, and initially reversible renal failure associated with the use of calcineurin inhibitors such as cyclosporin A or tacrolimus. In its acute form, CNI is characterized in that renal vasoconstriction results in reduced glomerular filtration rate and mainly impaired renal tubular function. In its chronic form, there are hemodynamic changes of the kidney in addition to other fibrosis, hyperplasia and vascular changes in the kidney such as interstitial fibrosis, tubular atrophy, glomerular fibrosis and arterial hyalinosis. . CNI is thought to be secondary to upregulation of endothelin, activation of the renin-angiotensin-aldosterone system, and subsequent chronic ischemia of the kidney. Clinically, the disease is characterized by elevated systemic blood pressure, electrolyte disorders and hyperuricemia.

  A series of experiments in animals and humans are summarized in Raina et al. (Transplant. J., vol. 94, no. 9, 2012, pp. 885-893) to counteract the effects of calcineurin inhibitors after kidney transplantation. Support the potential role of Ambrisentan. The doses of ambrisentan referenced and used in human studies are 5 and 10 mg / day, resulting in plasma levels greater than 350 ng / ml. The authors show the absence of pharmacokinetic interactions between ambrisentan and cyclosporin A and tacrolimus as a further basis for the role of ambrisentan in the prevention of the calcineurin inhibitor nephrotoxicity.

  In a further paper by Zhang et al. (European review for medical & pharmacological science, 2014, 18, pp. 2575-2583), the results obtained with co-administration of tacrolimus and ambrisentan in rats were that ambrisentan was at least partially Indicates that tacrolimus nephrotoxicity can be counteracted. The dose of ambrisentan used in this study is 0.5 mg / kg / day, allometrically corresponding to 35 mg per day in humans.

SUMMARY Although we have determined that certain types of acute renal failure block endothelin receptor subtype A (ETR-A) and its activity in the kidney, endothelin receptor subtype B (ETR-B) in the kidney We have found that it can be prevented and treated by administering a selective ETR-A antagonist in an amount that does not significantly block

  We interact with and antagonize ETR-B when the selective ETR-A antagonist is administered at doses approved for the treatment of other conditions such as pulmonary arterial hypertension. I found it further. In this regard, several ETR antagonists, such as ambrisentan and other compounds described below, have been approved for oral administration to treat pulmonary arterial hypertension. Some of these, including ambrisentan, are considered as selective ETR-A antagonists. However, despite its selectivity for ETR-A, their systemic administration in approved dosage forms is substantially too high to be purely ETR-A selective, and thus acute with renal vasoconstriction. It results in plasma levels that are too high to be effective for the prevention and treatment of renal failure.

  In particular, the formulations and methods of the present invention treat or prevent conditions that result in acute renal failure due to vasoconstriction, such as hepatorenal syndrome, liver disorders such as refractory ascites and dilute hyponatremia; graft function delay and Calcineurin inhibitor Treating or preventing complications due to kidney transplantation such as nephrotoxicity; Treating or preventing complications of radiation therapy such as contrast-induced acute kidney injury; Renal complications such as heart failure including heart failure syndrome Treating or preventing renal failure associated with solid organ transplantation; and treating or preventing renal complications of cardiac surgery such as acute renal injury after cardiac surgery. Furthermore, the formulations and methods of the invention are intended to support the diagnosis of renal failure in liver or kidney transplant candidates. To achieve the benefits of the present invention, new and improved formulations for selective ETR-A antagonists and new methods for their therapeutic use are needed. Thus, one object of the present invention is to provide new formulations of ETR-A antagonists and to provide new pharmaceutical uses of ETR-A antagonists.

Description of the Invention and Embodiments In a preferred embodiment, maintaining relatively low plasma concentrations of a selective ETR-A antagonist such as ambrisentan is effective in treating acute renal failure associated with renal vasoconstriction. It relates to the finding that If ETR-A is saturated with an antagonist, it is preferred that plasma concentrations of such ETR-A antagonists be monitored as even selective ETR-A antagonists can partially antagonize ETR-B . Blockade of the ETR-B receptor prevents vasodilation and formation of urine, so if the ETR-B receptor is also significantly antagonized, the clinical benefit provided by the ETR-A antagonist is diminished or completely eliminated. To disappear.

  The invention and its embodiments are described in more detail below.

Definition:
"Acute kidney injury after cardiac surgery" (AKICS) is a complication that occurs in the immediate post-operative period of a subject undergoing complex cardiac surgery. It is characterized by increased renal vascular resistance, decreased renal blood flow, and decreased glomerular filtration rate.

  “The amount effective to improve renal function” is such that the amount of the compound administered antagonizes ETR-A in or in the subject's kidney in order to sufficiently improve the subject's renal function It means to shut off. "Effective amount" or "effective amount" means an amount effective at the dose and duration necessary to achieve the desired therapeutic or prophylactic result. Such effective amounts can be expressed as a daily dose of endothelin receptor antagonist and / or blood levels of endothelin receptor antagonist, as discussed herein. In the case of hepatorenal disorders, in particular hepatorenal syndrome, refractory ascites and dilute hyponatremia, an effective dose is required to achieve an increase in urine volume over time, an increase in urinary sodium and / or a decrease in serum creatinine It is decided on the basis of In the case of graft function delay, the effective amount is determined based on the amount needed to achieve increased urine output and / or decreased serum creatinine or serum cystatin C during the immediate post-operative period, and As a result, the need for dialysis can be prevented. In the case of contrast-induced acute kidney injury, the effective amount is determined based on the amount necessary to achieve a reduction or normalization of serum creatinine or serum cystatin C immediately after the radiological procedure, resulting in dialysis Can prevent the need for In the case of cardiorenal syndrome, an effective amount is to achieve increased urine output, decreased or normalized urinary sodium and / or serum creatinine or serum cystatin C, and / or to achieve the prevention of the need for dialysis. Based on the amount required for In the case of acute kidney injury after cardiac surgery, an effective amount is based on the amount needed to achieve a reduction or normalization of serum creatinine or serum cystatin C immediately after surgery and / or to prevent the need for dialysis. It is determined. In the case of the calcineurin inhibitor nephrotoxicity (CNI), the effective amount is determined based on the amount required to achieve a reduction in systemic blood pressure and normalization of urinary metabolism or electrolyte abnormalities. In the case of renal failure associated with solid organ transplantation, an effective amount is the amount necessary to achieve reduction or normalization of serum creatinine or serum cystatin C and / or to prevent the need for dialysis in the post-transplant period It is decided based on. To identify whether the kidney suffers from vasoconstriction, the effective amount may be the same as the effective amount for treatment or prevention as described above; however, this amount affects renal function of the kidney. As far as possible, the effective amount may be even smaller. Such an effective amount can be determined based on the amount needed to challenge renal function by blocking endothelin-induced vasoconstriction. Such amounts will achieve changes in any renal function parameter indicating that renal function is higher than that observed prior to the diagnostic procedure. Such markers include, for example, changes in renal blood flow, changes in renal vascular resistance, increased urinary volume or urinary sodium, and changes in serum creatinine or serum cystatin C.

  "Calcineurin inhibitor nephrotoxicity" refers to the use of calcineurin inhibitors and includes acute or chronic reversible renal failure, renal vasoconstriction characterized clinically by elevated systemic blood pressure, electrolyte dysfunction and hyperuricemia means.

  "Cardiorenal syndrome" (CS) is a common renal complication that occurs in patients with heart failure and is characterized clinically by the retention of water and sodium. Some forms of CS are characterized by increased renal vascular resistance, decreased renal blood flow, decreased urinary and sodium excretion, and respond poorly to diuretic therapy.

  “Contrast agent-induced acute kidney injury” (CIAKI) is the administration of an iodine-based radiocontrast agent that occurs most frequently in subjects with existing renal failure, in elderly subjects, or in subjects treated with high amounts of contrast agent. Means later renal complications. CIAKI is characterized by increased renal vascular resistance and decreased glomerular filtration rate.

  The phrase "does not significantly antagonize endothelin receptor type B" means that the administered compound does not antagonize ETR-B at all or does not antagonize any adverse renal effects such as fluid retention to patients. Means If ETR-B is significantly antagonized, improved renal function caused by antagonizing ETR-A is not observed or not completely offset. Such antagonism of ETR-B can be established by measuring the concentration of endothelin in blood. If ETR-B is not blocked by the antagonist, the endothelin concentration is the same as before treatment. If ETR-B is completely blocked, the endothelin concentration after antagonist treatment will be higher than the level measured before treatment. For preferential ETR-A blockade, the endothelin concentration in the blood is at most 150% of the pre-treatment endothelin concentration, more preferably 130% or less, more preferably 120% or less of the pre-treatment endothelin concentration, 110 % Or less is more preferable. Most preferably, the endothelin concentration is the same as the blood concentration after treatment with a selective ETR-A antagonist.

  A "liver disorder" is progressive or rapidly progressive in a subject with existing progressive liver failure (eg, caused by cirrhosis with or without ascites) or acute liver failure, or in a subject who has liver transplantation. Mean a condition characterized by functional renal failure. Hepatic nephropathy includes conditions such as hepatorenal syndrome, refractory ascites and dilute hyponatremia.

  “Improving renal function” (and variants thereof, eg, “improvement of renal function”) means that the subject who receives the compound and preparation of the present invention exhibits clinical improvement of renal function Do. Such improvements include, for example, increased urine output, increased urinary sodium, decreased urinary endothelin, decreased serum creatinine, decreased renal vasoconstriction, decreased renal hypertension, decreased fluid retention and edema, And may be accompanied by beneficial changes in renal function such as reduced or delayed mortality. For example, patients treated in accordance with the present invention can increase their daily urine volume from about 200-500 ml to over 1 liter. In the case of hepatorenal disorders, in particular hepatorenal syndrome, refractory ascites and dilute hyponatremia, improvement in renal function may be indicated by increased urine volume and urinary sodium, or decreased serum creatinine or serum cystatin C. In the case of delayed graft function, an improvement in renal function may be indicated by an increase in urine output immediately after surgery, a decrease or normalization of serum creatinine or cystatin C, and a decrease in urinary endothelin. In the case of contrast agent-induced acute kidney injury, an improvement in renal function may be indicated by an increase in glomerular filtration rate or a decrease in serum creatinine. In the case of acute kidney injury after cardiac surgery, improved renal function may be indicated by an increase in glomerular filtration rate or a decrease in serum creatinine. In the case of cardiorenal syndrome, improved renal function may be indicated by increased urine and sodium, decreased serum creatinine and / or increased glomerular filtration rate. In the case of the calcineurin inhibitor nephrotoxicity, an improvement in renal function may be indicated by a normalization of systemic blood pressure and / or an improvement in renal electrolyte damage. In the case of renal failure associated with solid organ transplantation, improved renal function may be indicated by normalization of serum creatinine or an increase in glomerular filtration rate. In order to identify whether the kidney suffers from vasoconstriction, an improvement in renal function may be indicated by changes in any renal function parameter indicating that the function of the kidney is higher than that observed prior to the diagnostic procedure . Such markers include, for example, changes in renal blood flow, changes in renal vascular resistance, increased urinary volume or urinary sodium, and changes in serum creatinine or serum cystatin C.

  An "individual" or "subject" or "patient" is a mammal. Mammals include domestic animals (eg, cows, sheep, cats, dogs, and horses), primates (eg, non-human primates such as humans and monkeys), rabbits, and rodents (eg, mice and rats) But not limited to. In a preferred embodiment, the individual or subject is a human.

  “Liquid composition for parenteral administration” or “liquid preparation for parenteral administration” are suitable for intravenous, intraperitoneal, subcutaneous and / or intramuscular administration, and the ETR antagonist contained therein Etc. means a formulation which is in such a form as to effect the biological activity of the active ingredient, and which does not contain additional ingredients that are unacceptably toxic to the subject to whom the formulation is administered. These terms include both compositions that can be administered directly to a subject, as well as compositions that need to be diluted in conventional parenteral carrier solutions. Liquid compositions for intravenous, intraperitoneal, subcutaneous or intramuscular administration can have the same components in the same amount, but different components and different amounts of compositions are also contemplated.

  "Renal failure associated with solid organ transplantation" means renal complications after organ transplantation, characterized by increased renal vascular resistance and decreased glomerular filtration rate and / or increased serum creatinine.

  By "solid organ" is meant a mammalian organ such as the liver, heart, lung or kidney.

  By "substantially continuous" is meant that the administration of the compounds and formulations according to the invention is constant or intermittent as long as the indicated blood concentration of the ETR-A inhibitor is maintained or the intended benefit is obtained. Mean that it can be

  "Treatment" (and "alterations such as" treat "or" treating ") and" prevention "(and alteration such as" preventing "or" preventing ") are treated Refers to clinical intervention in an attempt to alter the natural history of the pathological condition of an individual, which can be performed for prophylaxis or during the course of clinical pathology. Desirable effects of treatment include preventing the onset or recurrence of the disease, alleviating symptoms, reducing the direct or indirect pathological consequences of the disease, reducing the rate of disease progression, improving or alleviating the disease state, and remission or These include, but are not limited to, improved prognosis.

Treatment of Acute Renal Failure:
Various ETR antagonists are known, including, for example, selective ETR-A antagonists such as sitaxsentan, ambrisentan, atrasentan, BQ-123, divotentan, bosentan, mathetiantan, tezosentan and darsentan. Preferred endothelin receptor antagonists are sitaxentan, ambrisentan, atrasentan, bosentan and masitentan. More preferred endothelin receptor antagonists are atrasentan, dibotentan and ambrisentan. Still more preferred endothelin receptor antagonists are atrasentan and ambrisentan. The most preferred antagonist is ambrisentan. None of these have been approved for the treatment of acute renal failure associated with renal vasoconstriction. Instead, some of these are approved or candidates for the treatment of pulmonary arterial hypertension (PAH) or are candidates for the treatment of diabetic nephropathy.

  In contrast to the methods and formulations of the present invention, approved doses and formulations of such PAH therapeutic compounds have plasma levels that significantly antagonize renal ETR-B as well as ETR-A in subjects with acute renal failure. In addition to the inhibition of fluid drainage by the kidney, it has no effect on renal vasoconstriction, or an increase rather than a decrease in renal vasoconstriction. For example, ambrisentan, which is sold in the United States under the trade name Letaris® (in Europe, Volibris®), has been approved for oral administration at an active ingredient content of 5 mg or 10 mg. Plasma levels after a single dose of Letairis® often reach 700 ng / ml, and are generally found in the range of about 350 ng / ml or 670 ng / ml for 5 mg and 10 mg doses, respectively. Such levels are actually counterproductive because they are too high to be effective in treating acute renal failure and may contribute to renal vasoconstriction and renal failure.

  With the currently approved oral administration of ambrisentan, blood levels rise immediately after ingestion and fall over time, achieving a constant level that is repeated with each subsequent oral administration to the subject Is a cycle that makes it difficult to Patients can also experience an initial drop in blood pressure. Even if given orally with an active ingredient content lower than that approved by Letairis®, the subject is treated with loading dose effects, ie plasma that adversely affects both types of ETR Experience an initial rise in levels.

  In addition, upon daily administration of the antagonist to the subject, the trough concentration of the antagonist, preferably ambrisentan, is increased to a level sufficiently above the initial (day 1) dose level. Subjects who develop acute renal failure associated with renal vasoconstriction often suffer from liver dysfunction and sometimes existing renal dysfunction. Because of this complication, this patient population can not effectively metabolize the administered drug, resulting in higher drug accumulation compared to subjects without kidney or liver damage. Thus, when administered daily for oral administration approved for PAH, the blood concentration of ambrisentan steadily increases over several days to a base level well above the desired effective concentration used in the present invention Will. These high concentrations result in blockade of endothelin B receptor sites and, conversely, can cause renal side effects.

  Also, patients with liver disease have elevated levels of freely available drugs in general, as levels of total protein in blood, especially albumin, are reduced and drugs often do not bind to circulating proteins present in blood. Do. Furthermore, the active ingredients when administered orally in the form of tablets are absorbed differently in the digestive tract of different subjects, complicating the attainment of stable blood concentration levels.

  For all these reasons, Letaris® and other compounds approved to treat PAH when administered in approved dosage forms and active ingredient content treat acute kidney failure Not valid for In addition, the use of approved PAH therapy to treat acute renal failure is detrimental to renal function and may exacerbate renal failure.

  Thus, the methods and formulations of the present invention contemplate the use of ETR-A antagonists to achieve much lower concentrations than would be appropriate for approved treatment of other conditions such as PAH. In addition, preferred embodiments of the present invention also include parenteral routes of administration, in particular intravenous routes.

  (Not described in the original text)

  In a preferred embodiment, the present invention relates to the use of ambrisentan or a liquid composition comprising ambrisentan in the treatment of hepatorenal syndrome, wherein ambrisentan is maintained at plasma levels of ambrisentan below about 100 ng / ml. As administered to the subject. Thus, the present invention relates to ambrisentan for use in the treatment of hepatorenal syndrome, wherein ambrisentan is administered to a subject such that the plasma level of ambrisentan is maintained below about 100 ng / ml. . Furthermore, the present invention treats a subject suffering from hepatorenal syndrome, including administering an effective amount of ambrisentan to the subject and intravenously administering the ambrisentan or a liquid composition containing ambrisentan. A method is provided, wherein ambrisentan is administered to a subject such that the plasma level of ambrisentan is maintained below about 100 ng / ml.

  In a preferred embodiment, the invention relates to the use of ambrisentan or a liquid composition comprising ambrisentan in the prevention of hepatorenal syndrome, wherein ambrisentan is maintained at plasma levels of ambrisentan below about 100 ng / ml. As administered to the subject. Thus, the present invention relates to ambrisentan for use in the treatment of a subject at risk of developing hepatorenal syndrome, wherein ambrisentan maintains plasma level of ambrisentan below about 100 ng / ml. Be administered to the subject to be treated. Furthermore, the present invention relates to a subject at risk for developing liver-renal syndrome, which comprises administering an effective amount of ambrisentan to a subject and intravenously administering a liquid composition containing ambrisentan or ambrisentan. Provide a method for prophylactically treating a subject, wherein ambrisentan is administered to a subject such that the plasma level of ambrisentan is maintained below about 100 ng / ml.

  In a preferred embodiment, the present invention relates to the use of ambrisentan or a liquid composition comprising ambrisentan in the treatment of hepatorenal syndrome, wherein ambrisentan is maintained at plasma levels of ambrisentan below about 100 ng / ml. As administered to the subject. Thus, the present invention relates to ambrisentan for use in the treatment of hepatorenal disorder, wherein ambrisentan is administered to a subject such that the plasma level of ambrisentan is maintained below about 100 ng / ml. . Furthermore, the present invention treats a subject suffering from hepatorenal syndrome, including that an effective amount of ambrisentan is administered to the subject and the liquid composition containing ambrisentan or ambrisentan is parenterally administered. A method is provided, wherein ambrisentan is administered to a subject such that the plasma level of ambrisentan is maintained below about 100 ng / ml.

  In a preferred embodiment, the present invention relates to the use of ambrisentan or a liquid composition comprising ambrisentan in the prevention of hepatorenal injury, wherein ambrisentan is maintained at plasma levels of ambrisentan below about 100 ng / ml. As administered to the subject. Thus, the present invention relates to ambrisentan for use in the treatment of a subject who is at risk of developing hepatorenal disorder, wherein ambrisentan maintains plasma level of ambrisentan below about 100 ng / ml. Be administered to the subject to be treated. Furthermore, the present invention relates to a subject at risk of developing liver kidney injury, which comprises administering to a subject an effective amount of ambrisentan and parenterally administering a liquid composition containing ambrisentan or ambrisentan. Provide a method for prophylactically treating a subject, wherein ambrisentan is administered to a subject such that the plasma level of ambrisentan is maintained below about 100 ng / ml.

  In a preferred embodiment, the invention relates to the use of ambrisentan or a liquid composition comprising ambrisentan in the treatment of refractory ascites, wherein ambrisentan is maintained at plasma levels of ambrisentan below about 100 ng / ml. Be administered to the subject to be treated. Thus, the present invention relates to ambrisentan for use in the treatment of refractory ascites, wherein ambrisentan is administered to a subject such that the plasma level of ambrisentan is maintained below about 100 ng / ml. Ru. In addition, the present invention treats a subject suffering from refractory ascites fluid, which comprises administering to the subject an effective amount of ambrisentan and parenterally administering a liquid composition containing ambrisentan or ambrisentan. Provided that the ambrisentan is administered to the subject such that the plasma level of ambrisentan is maintained below about 100 ng / ml.

  In a preferred embodiment, the present invention relates to the use of ambrisentan or a liquid composition comprising ambrisentan in the prevention of refractory ascites, wherein ambrisentan is maintained at plasma levels of ambrisentan below about 100 ng / ml. Be administered to the subject to be treated. Thus, the present invention relates to ambrisentan for use in the treatment of a subject who is at risk of developing refractory ascites, wherein ambrisentan has plasma levels of ambrisentan less than about 100 ng / ml. Administered to the subject to be maintained. Furthermore, the present invention has the potential risk of developing refractory ascites, including that an effective amount of ambrisentan is administered to a subject and the liquid composition containing ambrisentan or ambrisentan is administered parenterally. A method is provided for prophylactically treating a subject, wherein ambrisentan is administered to a subject such that plasma level of ambrisentan is maintained below about 100 ng / ml.

  In a preferred embodiment, the invention relates to the use of ambrisentan or a liquid composition comprising ambrisentan in the treatment of dilute hyponatremia, wherein ambrisentan has a plasma level of ambrisentan less than about 100 ng / ml. Administered to the treatment subject to be maintained. Thus, the present invention relates to ambrisentan for use in the treatment of dilute hyponatremia, wherein ambrisentan is a treated subject such that the plasma level of ambrisentan is maintained below about 100 ng / ml. Administered to Furthermore, the present invention relates to a subject suffering from dilutable hyponatremia comprising an effective amount of ambrisentan being administered to a subject and parenterally administering a liquid composition comprising ambrisentan or ambrisentan. Provide a method of treating a subject, wherein ambrisentan is administered to the subject such that the plasma level of ambrisentan is maintained below about 100 ng / ml.

  In a preferred embodiment, the invention relates to the use of ambrisentan or a liquid composition comprising ambrisentan in the prevention of dilute hyponatremia, wherein ambrisentan has a plasma level of ambrisentan below about 100 ng / ml. Administered to the treatment subject to be maintained. Thus, the present invention relates to ambrisentan for use in the treatment of a subject at risk of developing dilute hyponatremia, wherein ambrisentan has a plasma level of ambrisentan of about 100 ng / Administered to the subject to be maintained at less than ml. Furthermore, the present invention is capable of the risk of developing diluteable hyponatremia, including that an effective amount of ambrisentan is administered to a subject and the liquid composition containing ambrisentan or ambrisentan is parenterally administered. A method is provided for prophylactically treating a subject having a sex, wherein ambrisentan is administered to a subject such that plasma levels of ambrisentan are maintained below about 100 ng / ml.

  In a preferred embodiment, the present invention relates to the use of ambrisentan or a liquid composition comprising ambrisentan in the treatment of graft function delay, wherein ambrisentan maintains plasma level of ambrisentan below about 100 ng / ml. Be administered to the subject to be treated. Thus, the present invention relates to ambrisentan for use in the treatment of graft function delay, wherein ambrisentan is administered to a subject such that plasma level of ambrisentan is maintained below about 100 ng / ml. Be done. Furthermore, the present invention provides a subject suffering from graft function delay, which comprises administering to the subject an effective amount of ambrisentan and parenterally administering a liquid composition containing ambrisentan or ambrisentan. A method of treating is provided, wherein ambrisentan is administered to a subject such that the plasma level of ambrisentan is maintained below about 100 ng / ml.

  In a preferred embodiment, the invention relates to the use of ambrisentan or a liquid composition comprising ambrisentan in the prevention of delayed graft function after kidney transplantation, wherein ambrisentan has a plasma level of ambrisentan of about 100 ng / gram. Administered to the subject to be maintained at less than ml. Thus, the present invention relates to ambrisentan for use in the treatment of a subject who is at risk of developing graft function delay after kidney transplantation, wherein ambrisentan has a plasma level of ambrisentan of about It is administered to the subject to be maintained at less than 100 ng / ml. Furthermore, the present invention relates to transplantation after kidney transplantation, which comprises administering an effective amount of ambrisentan to a subject and parenterally, preferably intravenously administering a liquid composition containing ambrisentan or ambrisentan Provided is a method for prophylactically treating a subject who is likely to develop a delayed function, wherein ambrisentan is treated to maintain plasma level of ambrisentan below about 100 ng / ml Administered to the subject.

  In a preferred embodiment, the present invention relates to the use of ambrisentan or a liquid composition comprising ambrisentan in the treatment of renal failure associated with solid organ transplantation, wherein ambrisentan has a plasma level of ambrisentan of about 100 ng / ml. Administered to the subject so as to be maintained below. Thus, the present invention relates to ambrisentan for use in the treatment of renal failure associated with solid organ transplantation, wherein ambrisentan is treated such that the plasma level of ambrisentan is maintained below about 100 ng / ml. Administered to Furthermore, the present invention suffers from renal failure associated with solid organ transplantation, including that an effective amount of ambrisentan is administered to a subject and the liquid composition containing ambrisentan or ambrisentan is parenterally administered. Provided is a method of treating a subject, wherein ambrisentan is administered to the subject such that the plasma level of ambrisentan is maintained below about 100 ng / ml.

  In a preferred embodiment, the present invention relates to the use of ambrisentan or a liquid composition comprising ambrisentan in the prevention of renal failure associated with solid organ transplantation, wherein ambrisentan has a plasma level of ambrisentan of about 100 ng / ml. Administered to the subject so as to be maintained below. Thus, the present invention relates to ambrisentan for use in treating a subject who is at risk of developing renal failure associated with solid organ transplantation, wherein ambrisentan has a plasma level of ambrisentan of about 100 ng. Administered to the treatment subject to be maintained at less than / ml. Furthermore, the present invention relates to solid organ transplantation, which comprises administering an effective amount of ambrisentan to a subject and parenterally, preferably intravenously administering a liquid composition containing ambrisentan or ambrisentan Provided is a method for prophylactically treating a subject who may develop renal failure, wherein ambrisentan is treated such that plasma level of ambrisentan is maintained below about 100 ng / ml. Administered to

  In a preferred embodiment, the present invention relates to the use of ambrisentan or a liquid composition comprising ambrisentan in the treatment of calcineurin inhibitor nephrotoxicity, wherein ambrisentan has plasma levels of ambrisentan below about 100 ng / ml. Administered to the subject to be maintained. Thus, the present invention relates to ambrisentan for use in the treatment of calcineurin inhibitor nephrotoxicity, wherein ambrisentan is administered to the subject such that the plasma level of ambrisentan is maintained below about 100 ng / ml. It is administered. Furthermore, the present invention relates to a subject suffering from a calcineurin inhibitor nephrotoxicity, comprising an effective amount of ambrisentan being administered to a subject and parenterally administering a liquid composition containing ambrisentan or ambrisentan. Provided that the ambrisentan is administered to the subject such that the plasma level of ambrisentan is maintained below about 100 ng / ml.

  In a preferred embodiment, the present invention relates to the use of ambrisentan or a liquid composition comprising ambrisentan in the prevention of calcineurin inhibitor nephrotoxicity, wherein ambrisentan has plasma levels of ambrisentan below about 100 ng / ml. Administered to the subject to be maintained. Thus, the present invention relates to ambrisentan for use in the treatment of a subject who is at risk of developing a calcineurin inhibitor nephrotoxicity, wherein ambrisentan has a plasma level of ambrisentan of about 100 ng / ml. Administered to the subject so as to be maintained below. Furthermore, the present invention provides the potential risk of developing the calcineurin inhibitor nephrotoxicity, including that an effective amount of ambrisentan is administered to the subject and the liquid composition containing ambrisentan or ambrisentan is administered parenterally. Provide a method for prophylactically treating a subject, wherein ambrisentan is administered to a subject such that plasma level of ambrisentan is maintained below about 100 ng / ml.

  In a preferred embodiment, the present invention relates to the use of ambrisentan or a liquid composition comprising ambrisentan in the treatment of contrast agent-induced acute kidney injury, wherein ambrisentan has a plasma level of ambrisentan of about 100 ng / ml. Administered to the subject so as to be maintained below. Thus, the present invention relates to ambrisentan for use in the treatment of contrast-induced acute kidney injury, wherein ambrisentan is treated such that the plasma level of ambrisentan is maintained below about 100 ng / ml. Administered to Furthermore, the present invention suffers from contrast agent-induced acute kidney damage, which comprises administering to the subject an effective amount of ambrisentan and parenterally administering a liquid composition containing ambrisentan or ambrisentan Provided is a method of treating a subject, wherein ambrisentan is administered to the subject such that the plasma level of ambrisentan is maintained below about 100 ng / ml.

  In a preferred embodiment, the present invention relates to the use of ambrisentan or a liquid composition comprising ambrisentan in the prevention of contrast agent-induced acute kidney injury, wherein ambrisentan has a plasma level of ambrisentan of about 100 ng / ml. Administered to the subject so as to be maintained below. Thus, the present invention relates to ambrisentan for use in the treatment of a subject who is at risk of developing contrast agent-induced acute kidney injury, wherein ambrisentan has a plasma level of ambrisentan of about 100 ng. Administered to the treatment subject to be maintained at less than / ml. Furthermore, the present invention is directed to the risk of developing contrast agent-induced acute kidney injury, which comprises administering to a subject an effective amount of ambrisentan and parenterally administering a liquid composition containing ambrisentan or ambrisentan. A method is provided for prophylactically treating a potential subject, wherein ambrisentan is administered to a subject such that the plasma level of ambrisentan is maintained below about 100 ng / ml. .

  In a preferred embodiment, the invention relates to the use of ambrisentan or a liquid composition comprising ambrisentan in the treatment of cardiorenal syndrome, wherein ambrisentan is maintained at plasma levels of ambrisentan below about 100 ng / ml. Be administered to the subject to be treated. Thus, the present invention relates to ambrisentan for use in the treatment of cardiorenal syndrome, wherein ambrisentan is administered to a subject such that the plasma level of ambrisentan is maintained below about 100 ng / ml. Ru. In addition, the present invention treats a subject suffering from cardiorenal syndrome, which comprises administering to the subject an effective amount of ambrisentan and parenterally administering a liquid composition containing ambrisentan or ambrisentan. Provided that the ambrisentan is administered to the subject such that the plasma level of ambrisentan is maintained below about 100 ng / ml.

  In a preferred embodiment, the invention relates to the use of ambrisentan or a liquid composition comprising ambrisentan in the prevention of cardiorenal syndrome, wherein ambrisentan is maintained at a plasma level of ambrisentan below about 100 ng / ml. Be administered to the subject to be treated. Thus, the present invention relates to ambrisentan for use in the treatment of a subject at risk of developing cardiorenal syndrome, wherein ambrisentan has a plasma level of ambrisentan less than about 100 ng / ml. Administered to the subject to be maintained. Furthermore, the present invention has the potential risk of developing cardiorenal syndrome, including that an effective amount of ambrisentan is administered to a subject and that the liquid composition containing ambrisentan or ambrisentan is administered parenterally. A method is provided for prophylactically treating a subject, wherein ambrisentan is administered to a subject such that plasma level of ambrisentan is maintained below about 100 ng / ml.

  In a preferred embodiment, the invention relates to the use of ambrisentan or a liquid composition comprising ambrisentan in the treatment of acute kidney injury after cardiac surgery, wherein ambrisentan has a plasma level of ambrisentan less than about 100 ng / ml Administered to the treatment subject to be maintained. Thus, the present invention relates to ambrisentan for use in the treatment of acute kidney injury after cardiac surgery, wherein ambrisentan is a treatment subject such that the plasma level of ambrisentan is maintained below about 100 ng / ml. Administered to Furthermore, the present invention relates to a subject suffering from acute kidney injury after cardiac surgery, which comprises that an effective amount of ambrisentan is administered to a subject and the liquid composition containing ambrisentan or ambrisentan is administered parenterally. Provide a method of treating a subject, wherein ambrisentan is administered to the subject such that the plasma level of ambrisentan is maintained below about 100 ng / ml.

  In a preferred embodiment, the invention relates to the use of ambrisentan or a liquid composition comprising ambrisentan in the prevention of acute kidney injury after cardiac surgery, wherein ambrisentan has a plasma level of ambrisentan less than about 100 ng / ml Administered to the treatment subject to be maintained. Thus, the present invention relates to ambrisentan for use in the treatment of a subject who is at risk of developing acute kidney injury after cardiac surgery, wherein ambrisentan has a plasma level of ambrisentan of about 100 ng / Administered to the subject to be maintained at less than ml. In addition, the present invention is capable of the risk of developing acute kidney injury after cardiac surgery, including that an effective amount of ambrisentan is administered to a subject and the liquid composition comprising ambrisentan or ambrisentan is parenterally administered. A method is provided for prophylactically treating a subject having a sex, wherein ambrisentan is administered to a subject such that plasma levels of ambrisentan are maintained below about 100 ng / ml.

  The present invention further relates to ambrisentan for use in the treatment of a subject suffering from a reduction in renal function and for identifying a reduction in renal function due to vasoconstriction, wherein ambrisentan is plasma of ambrisentan Administered to the treatment subject such that levels are maintained below about 100 ng / ml. Preferably, the present invention relates to ambrisentan for use in the treatment of a subject to identify whether the decrease in renal function is due to renal vasoconstriction, wherein ambrisentan is plasma of ambrisentan The subject is administered such that the level is maintained below about 100 ng / ml. In addition, the present invention includes that an effective amount of ambrisentan is administered to a subject, renal function is determined before and after treatment, and a liquid composition comprising ambrisentan or ambrisentan is intravenously administered. Provides a method of treating a subject suffering from loss of function and identifying a decrease in renal function due to vasoconstriction, wherein ambrisentan maintains plasma level of ambrisentan below about 100 ng / ml As administered to the subject.

  The invention further relates to ambrisentan for use in treating a subject to identify a decline in renal function, wherein ambrisentan is maintained at a plasma level of ambrisentan below about 100 ng / ml As such, it is administered to the subject. Preferably, the present invention relates to ambrisentan for use in the treatment of a subject to identify whether renal function is reduced, wherein ambrisentan has a plasma level of ambrisentan of about 100 ng / ml. Administered to the subject to be maintained below. In addition, the present invention includes subjecting an effective amount of ambrisentan to a subject, determining renal function before and after treatment, and intravenously administering a liquid composition comprising ambrisentan or ambrisentan, Provide a method of treating a subject and identifying a decrease in renal function, wherein ambrisentan is administered to the subject such that plasma level of ambrisentan is maintained below about 100 ng / ml.

  Currently, it is difficult to assess whether the kidney suffers from decreased renal function due to vasoconstriction. Traditionally, such assessments are widely performed by performing biopsies that are invasive, risky to the patient, and do not always provide a good assessment. The uses and methods of the present invention are non-invasive, easy to apply and pose a relatively low risk to the patient. The methods and uses of the present invention can replace or supplement a biopsy. The methods and uses of the present invention allow the kidney to be impaired by disease, eg, severe liver injury, resulting in vasoconstriction to the kidney and / or vasoconstriction in the kidney, and by itself or by Sentan treatment helps to identify if kidney function in the kidney is restored or kidney function is improved.

  The invention further relates to ambrisentan for use in the treatment of a subject suffering from hepatorenal disorder and for identifying reduced renal function due to vasoconstriction, wherein ambrisentan is a plasma level of ambrisentan It is administered to the subject such that the Tj is maintained below about 100 ng / ml. Preferably, the present invention relates to the use of ambrisentan for use in the treatment of a subject suffering from hepatorenal disorder and for identifying whether the reduction in renal function is due to vasoconstriction, wherein: Is administered to the subject such that the plasma level of ambrisentan is maintained below about 100 ng / ml. In addition, the present invention includes that an effective amount of ambrisentan is administered to a subject, renal function is determined before and after treatment, and a liquid composition comprising ambrisentan or ambrisentan is intravenously administered. Provides a method of treating a subject suffering from a disorder and identifying reduced renal function due to vasoconstriction, wherein ambrisentan is such that plasma level of ambrisentan is maintained below about 100 ng / ml Administered to the subject being treated.

  The present invention is further directed to ambrisentan for use in the treatment of a subject waiting for liver transplantation and for identifying reduced renal function, wherein ambrisentan has a plasma level of ambrisentan of about 100 ng / Administered to the subject to be maintained below ml. Preferably, the present invention relates to ambrisentan for use in the treatment of a subject awaiting liver transplantation and for identifying reduced renal function, wherein ambrisentan has a plasma level of ambrisentan of about Administered to the treatment subject to be maintained at less than 100 ng / ml. Furthermore, the present invention includes that an effective amount of ambrisentan is administered to a subject, renal function is determined before and after treatment, and a liquid composition containing ambrisentan or ambrisentan is intravenously administered. Provides a method of treating a subject awaiting transplantation and identifying reduced renal function, wherein ambrisentan is treated such that plasma level of ambrisentan is maintained below about 100 ng / ml Administered to

  The present invention is eligible for dual liver-kidney transplant waiting for liver transplantation, without improvement in renal function in the subject, preferably for treating subjects in whom kidney is transplanted Ambrisentan, wherein ambrisentan is administered to the subject such that the plasma level of ambrisentan is maintained below about 100 ng / ml. Preferably, the present invention is a subject awaiting liver transplantation, without improvement in renal function in the subject, is eligible for dual liver-kidney transplant, preferably kidney Regarding ambrisentan for use in treatment of a transplanted subject, wherein ambrisentan is administered to the subject such that the plasma level of ambrisentan is maintained below about 100 ng / ml. Furthermore, the present invention includes that an effective amount of ambrisentan is administered to a subject, renal function is determined before and after treatment, and a liquid composition containing ambrisentan or ambrisentan is intravenously administered. Treating a subject with no improvement in renal function in the subject who is awaiting transplantation, who is eligible for dual liver-kidney transplantation, preferably in which kidney is to be transplanted Provided is a method of identifying reduced renal function, wherein ambrisentan is administered to a subject such that plasma level of ambrisentan is maintained below about 100 ng / ml. The methods and uses of the present invention enable the surgeon and / or medical team performing liver transplantation to determine if kidney transplantation is necessary, or that the kidneys retain their original condition after liver transplantation, or are acceptable and improved It provides an easy and non-invasive method to determine if you have a reasonable opportunity to obtain renal function.

  The present invention is further directed to ambrisentan for use in the treatment of a subject who has previously undergone kidney transplantation, and for identifying reduced renal function, wherein ambrisentan has a plasma level of ambrisentan of about It is administered to the subject to be maintained at less than 100 ng / ml. Preferably, the present invention relates to ambrisentan for use in the treatment of a subject who has previously received kidney transplantation, and for identifying a decline in renal function, wherein ambrisentan is a plasma level of ambrisentan It is administered to the subject such that is maintained at less than about 100 ng / ml. Furthermore, the present invention includes that an effective amount of ambrisentan is administered to the subject, renal function is determined before and after treatment, and the liquid composition containing ambrisentan or ambrisentan is intravenously administered, Provide a method of treating a subject undergoing kidney transplantation and identifying decreased renal function, wherein ambrisentan is treated such that plasma level of ambrisentan is maintained below about 100 ng / ml Administered to the subject. This method and use of the present invention allows the physician to determine and determine if further treatment with ambrisentan is necessary to improve the likelihood of successful kidney transplantation.

  The above embodiments also apply to divotentane and atrasentan, including their individual embodiments.

Therapeutic levels of ETR-A antagonists:
In a preferred embodiment of the invention, the ETR-A antagonist is ambrisentan. For the purposes of the present invention, ambrisentan preferably has a plasma level of the compound of less than about 100 ng / ml, preferably less than about 75 ng / ml, more preferably less than about 50 ng / ml, even more preferably Is administered to the subject such that it is maintained at less than about 40 ng / ml, even more preferably less than about 25 ng / ml, and most preferably less than about 20 ng / ml, generally ambrisentan Plasma levels of at least 0.1 ng / ml, preferably at least 0.2 ng / ml, more preferably at least 0.3 ng / ml, even more preferably at least 0.5 ng / ml, even more preferably at least 1 ng / ml, and most preferably At least 5 ng / ml. The plasma level of ambrisentan indicates the concentration of total ambrisentan in plasma, including both ambrisentan bound to proteins present in blood and free unbound ambrisentan present in blood. Plasma levels or concentrations of both bound and non-bound ambrisentan can be determined using conventional techniques.

  In a further embodiment, ambrisentan has a plasma level of free (i.e. not bound to protein) ambrisentan of at most 1 ng / ml, preferably at most 0.8 ng / ml, more preferably at most 0.5 ng / Even more preferably still at most 0.4 ng / ml and most preferably at most 0.2 ng / ml and generally at least 0.001 ng / ml, preferably at least 0.005 ng / ml, more preferably at least 0.01 ng / ml Administered to the subject to be ml, even more preferably at least 0.05 ng / ml, and most preferably at least 0.1 ng / ml. Plasma levels or concentrations of free ambrisentan in plasma can be determined by separating ambrisentan bound to proteins and determining ambrisentan concentration using conventional analytical techniques.

  In one embodiment of the invention, the administration rate of the ETR-A antagonist, preferably ambrisentan, is equal to or substantially equal to the rate at which the antagonist, preferably ambrisentan is excreted from the blood. Thus, in contrast to the accumulation observed during the treatment of PAH described above, the concentration of antagonist in plasma does not accumulate. For example, excretion of ambrisentan proceeds through the subject's kidney and / or liver, and the excretion rate depends on the plasma concentration of ambrisentan.

Administration protocol:
The ETR-A antagonists of the invention are intended to be administered for a time such administration improves renal function and provides a clinical benefit. If an ETR-A antagonist, particularly ambrisentan, is used to treat acute renal failure that is transient, eg, DGF or calcineurin inhibitor nephrotoxicity, the ETR-A antagonist may be up to about 14 days For a period of time, preferably, up to about 10 days, more preferably, about 3 to 5 days, most preferably, about 4 days. And, administration of the ETR-A antagonist is substantially continuous when administered intravenously.

  However, the physician may choose to administer the ETR-A antagonist, for example, in a repeating cycle of 4 days, with one or more intervening days on which the compound is not administered.

  If an ETR-A antagonist, in particular ambrisentan, is used for the treatment of renal failure that may be persistent, for example in the treatment of hepatorenal disorder or cardiorenal syndrome, the ETR-A antagonist is routinely administered over an extended period of time It will The long term may be a solid organ, such as a period before, during and / or after kidney or liver transplantation, or treatment may be extended until the patient dies.

Formulation:
A preferred formulation of an ETR-A antagonist according to the invention, preferably amblysentan, is intravenous injection. Other forms of parenteral administration such as subcutaneous, transdermal, intraperitoneal and intramuscular are also contemplated. In these forms, subcutaneous is preferred. Dosing not administered orally has the further advantage of being appropriate for non-ingestible subjects, such as subjects suffering from neurological deficits or hepatic encephalopathy or subjects with anesthesia or similar conditions. Parenteral administration has the advantage that the antagonist is more effective in a shorter period of time than alternative administration methods and can easily reach the desired blood levels. Furthermore, the dose can be adjusted in the simple manner required, taking into account the subject's metabolic and functional characteristics.

  The invention further relates to a liquid composition for parenteral administration comprising an endothelin receptor antagonist, a buffer and a solvent. Preferably, the present invention relates to a liquid composition for parenteral administration comprising ambrisentan, a buffer and a solvent.

  It is preferred that the liquid composition of the present invention be substantially free of particles. More preferably, the liquid composition of the present invention does not contain particles. By "particles" is meant any type of solid, such as particles of endothelin receptor antagonists, dust particles or polymer particles. The term "substantially free of particles" means solid particles as defined in the Pharmacopoeia and present in acceptable amounts and sizes according to regulatory standards.

  The liquid composition of the present invention may be lyophilized.

  In one embodiment of the invention, the liquid composition comprises an endothelin receptor antagonist, preferably ambrisentan, in an amount of at most 15% by weight (wt%), based on the total weight of the liquid composition. The endothelin receptor antagonist, preferably ambrisentan, is at most 10 wt%, more preferably at most 5 wt%, even more preferably at most 2 wt% and most preferably at most 1 wt% based on the total weight of the liquid composition %, And preferably at least 0.0001 wt.%, More preferably at least 0.001 wt.%, Even more preferably at least 0.005 wt.% And most preferably at least 0.01 wt.%.

  In one embodiment of the invention, the liquid composition comprises a buffer in an amount of at most 15% by weight (wt%), based on the total weight of the liquid composition. The buffer is at most 10 wt%, more preferably at most 8 wt%, even more preferably at most 7 wt% and most preferably at most 5 wt%, and preferably at least 0.01 wt%, based on the total weight of the liquid composition %, More preferably at least 0.1 wt.%, Even more preferably at least 0.5 wt.%, And most preferably at least 1 wt.%.

  As solvents suitable for use in the composition according to the invention, water; alcohols such as ethanol, glycerine; polyethylene glycols such as PEG 300, PEG 400 and PEG 600; propylene glycol, N-methyl-2-pyrrolidone, and their solvents A combination of two or more may be mentioned. Of these solvents, preference is given to water, ethanol, propylene glycol and polyethylene glycol, or a combination mainly comprising any of these solvents. In another preferred embodiment, the composition of the present invention does not contain water as a solvent, and it is more preferred that the composition does not contain water.

  One embodiment of the present invention comprises the solvent in an amount of at least 85% by weight (wt%), based on the total weight of the liquid composition. The solvent is at least 90 wt%, and most preferably at least 92 wt%, and preferably at most 99.9 wt%, more preferably at most 98 wt%, and most preferably at most 95 wt%, based on the total weight of the liquid composition It is preferred to be present in an amount of Typically, the total amount of endothelin receptor antagonist, buffer, solvent and additional excipients (if present) is increased to 100% by weight in the liquid composition of the present invention.

  When a buffer is present in the liquid composition, the buffer used in the composition of the present invention may be any buffer known in the art that can be suitably used for parenteral administration. Buffering agents generally serve to maintain the composition at a constant pH, especially upon storage and when the composition is diluted appropriately. In one embodiment of the present invention, the buffer has a pH of the composition generally between 6 and 12, preferably at least 6.5, more preferably at least 7 and preferably at high pH of the composition. It is chosen to be at least 10, and more preferably at most 9. Compositions containing ambrisentan having a pH of at least 9 at least are particularly preferred, as these compositions typically have better stability and can have higher concentrations of ambrisentan. .

  In an embodiment of the present invention, the pH of the parenteral composition obtained after adding the concentrated liquid composition of the present invention is generally between 6 and 12, at least 6.5, more preferably at least 7 and at least Preferably, it is at most 9, and more preferably at most 8.

  Examples of suitable buffers include ammonium acetate, arginine, sodium benzoate, disodium citrate, trisodium citrate, diethanolamine, hydrobromic acid, monoethanolamine, phosphoric acid, monobasic sodium phosphate, phosphoric acid Sodium dihydrogen, tribasic sodium phosphate, monobasic potassium phosphate, potassium dihydrogen phosphate, tris (hydroxymethyl) methylamine (tromethamine or tris), 4-2-hydroxyethyl-1-piperazine ethane sulfonic acid (HEPES), and 2 (R) -2- (methylamino) succinic acid, and combinations of two or more of the above buffering agents. It is also conceivable to combine one or more of the above mentioned buffers with one or more buffers having a pKa of less than 6 and more than 10, as long as the overall pH of the composition of the invention is 6-10.

  The liquid composition can include other ingredients commonly used in liquid compositions for parenteral administration. When the liquid preparation of the present invention contains components other than endothelin receptor antagonist or ambrisentan, buffer and solvent, the total of other components such as endothelin receptor antagonist or ambrisentan, buffer, solvent and excipient The amount is up to 100% by weight of the total weight of the liquid composition.

  The composition of the present invention can further contain an excipient. Suitable excipients are known in the art. Such excipients include stabilizers and / or bulking agents such as mannitol, sucrose, trehalose, polyethylene glycol; isotonic agents such as dextrose, sodium chloride, glycerol, glycerin and mannitol; sodium carboxymethylcellulose, acacia, Viscosity enhancers or reducing agents such as gelatin, methylcellulose and polyvinylpyrrolidone; polyoxyethylene sorbitan monooleate (Tween 80), sorbitan monooleate, polyoxyethylene sorbitan monolaurate (Tween 20), polyoxyethylene polyoxypropylene Copolymers (Pluronics) and surfactants such as lecithin; disodium ethylenediaminetetraacetate (EDTA), disodium EDTA, sodium EDTA, calcium vercetamide Na, cal Chelates such as lidole and diethylenetriaminepentaacetic acid (DTPA); Antioxidants such as acetylcysteine, sulfites (bisulfite and metabisulfite); Antiphenols such as phenol, metacresol, benzyl alcohol, methyl paraben, propyl paraben and butyl paraben Microbial agents; and other adjuvants. It is understood that some excipients may have multiple properties.

  In one embodiment of the invention, the liquid composition comprises excipients in an amount of at most 15% by weight (% by weight), based on the total weight of the liquid composition. The buffer is at most 10 wt%, more preferably at most 8 wt%, even more preferably at most 7 wt% and most preferably at most 5 wt%, and preferably at least 0.01 wt%, based on the total weight of the liquid composition %, More preferably at least 0.1 wt.%, Even more preferably at least 0.5 wt.% And most preferably at least 1 wt.%.

  In a preferred embodiment, the liquid composition of the present invention is isotonic. In a preferred embodiment, the liquid composition of the present invention is sterile.

  Liquid compositions of the present invention may be prepared using conventional techniques. Typically, the present invention comprises the steps of: (a) contacting an endothelin receptor antagonist, preferably ambrisentan, a buffer and a solvent, and optionally an excipient; and (b) stirring the solution And (c) subsequently sterilizing the obtained solution; and (c) sterilizing the solution obtained. Step (a) of the process of the present invention may comprise the step of contacting all the components at one time or may comprise contacting the components sequentially, whereby one or more The process can be allowed to proceed at the same temperature or at different temperatures. For example, after first contacting at room temperature a component that is readily soluble in a solvent at room temperature and subsequently raising the temperature to, for example, 50 ° C., compounds of low solubility, eg, endothelin receptor such as ambrisentan Add an antagonist. Step (b) may proceed until the solid particles are not identified visually or by analytical techniques. The sterilization in step (c) of the method can be performed using any sterilization technique known in the art, such as filtration and autoclave sterilization. However, the use of autoclaves has generally been found to be undesirable as endothelin receptor antagonists, particularly ambrisentan, can degrade.

  Liquid compositions for parenteral administration include, but are not limited to, ampoules, vials, prefilled syringes, cartridges for subcutaneous pumps, cartridges for subcutaneous pens, drug reservoirs for subcutaneous pumps, or IV such as IV bags or bottles It can be provided in any suitable container, such as a container. The concentration of ETR-A receptor antagonist may vary depending on the container used to achieve improved renal function and clinical benefit.

  Liquid compositions can be administered directly to a subject. They may also be initially stored or formulated in a concentrated form which is diluted in an appropriate parenteral solution, such as a conventional physiological solution for intravenous administration, prior to administration. Suitable buffers, excipients and preservatives are conventional. Examples of such parenteral solutions include saline (sterile in sodium chloride), Ringer's lactic acid solution, Hartmann's solution (including sodium lactate), dextrose-containing solutions (such as D5W or D10W), and any of the above components. Solution (such as D5NS or D5LR).

  Liquid compositions can be added to conventional parenteral solutions using conventional techniques. The dilution factor of the endothelin receptor antagonist may be at least 5, which means, for example, adding 50 ml of the liquid composition of the invention to 200 ml of a conventional parenteral solution. Preferably, the dilution factor is at least 10 and most preferably at least 15, and generally at most 100, preferably at most 75, and most preferably at most 50.

  In general, it is intended that the person skilled in the art will adjust the amount of ETR-A (or ambrisentan) and formulation by conventional means suitable for administration to a particular subject.

  The above embodiments of the liquid composition of the present invention also apply to divotentan and atrasentan, including their individual embodiments.

Containers Comprising an ETR-A Antagonist The liquid composition of the present invention may be any suitable container, such as, but not limited to, ampoules, vials, prefilled syringes, cartridges for subcutaneous pens, drug reservoirs for subcutaneous pumps or IV bags. Can be provided. The concentration of endothelin receptor antagonist may vary depending on the container used. Thus, the invention further provides that the endothelin receptor antagonist, preferably ambrisentan, is typically at least 0.001 wt%, more preferably at least 0.01 wt%, even more preferably based on the total weight of the liquid composition Is at most 0.1 wt% and most preferably at least 0.2 wt%, and typically at most 5 wt%, preferably at most 3 wt%, more preferably at most 2 wt%, based on the total weight of the liquid composition It relates to an ampoule or vial containing a liquid composition according to the invention, which is even more preferably present at a concentration of at most 1 wt%, and most preferably at most 0.5 wt%.

  Thus, the present invention provides that the endothelin receptor antagonist, preferably ambrisentan, is typically at least 0.001 wt%, more preferably at least 0.01 wt%, and even more preferably, based on the total weight of the liquid composition. At least 0.02 wt% and most preferably at least 0.03 wt%, and typically at most 1 wt%, preferably at most 0.8 wt%, more preferably at most 0.6 wt%, based on the total weight of the liquid composition And, most preferably, to a prefilled syringe comprising the liquid composition of the present invention present at a concentration of at most 0.5 wt%.

  Thus, the present invention provides that the endothelin receptor antagonist, preferably ambrisentan, is typically at least 0.001 wt%, more preferably at least 0.01 wt%, and even more preferably, based on the total weight of the liquid composition. At least 0.02 wt% and most preferably at least 0.03 wt%, and typically at most 1 wt%, preferably at most 0.8 wt%, more preferably at most 0.6 wt%, based on the total weight of the liquid composition And a cartridge for a subcutaneous pump or a drug reservoir for a subcutaneous pump comprising the liquid composition of the invention, most preferably present at a concentration of at most 0.5 wt%.

  Thus, the present invention provides that the endothelin receptor antagonist, preferably ambrisentan, is typically at least 0.001 wt%, more preferably at least 0.01 wt%, and even more preferably, based on the total weight of the liquid composition. At least 0.02 wt% and most preferably at least 0.03 wt%, and typically at most 1 wt%, preferably at most 0.8 wt%, more preferably at most 0.6 wt%, based on the total weight of the liquid composition And a cartridge for a subcutaneous pen containing the liquid composition of the invention, most preferably present at a concentration of at most 0.5 wt%.

  Thus, the present invention provides that the endothelin receptor antagonist, preferably ambrisentan, is typically at least 0.00001 wt%, more preferably at least 0.0001 wt%, and even more preferably, based on the total weight of the liquid composition. At least 0.001 wt% and most preferably at least 0.002 wt%, and typically at least 0.00001 wt%, more preferably at least 0.0001 wt%, even more preferably at least 0.001 wt%, based on the total weight of the liquid composition And, most preferably, an IV container (such as an IV bag or bottle) containing the liquid composition of the present invention present at a concentration of at least 0.002 wt%.

  The above embodiments of the container also apply to divotentan and atrasentan, including their individual embodiments.

Pretreatment of the kidney for transplantation:
The invention further relates to the use of the liquid composition of the invention in the pre-treatment of the kidney for kidney transplantation. In addition, the present invention provides a method of pretreating the kidney with the liquid composition of the present invention, comprising the step of administering to the kidney a liquid composition of the present invention comprising an effective amount of an endothelin receptor antagonist. Preferably, the present invention is a method for pretreatment of the kidney with a liquid composition comprising ambrisentan or ambrisentan, wherein an effective amount of ambrisentan has a level of ambrisentan in the renal vasculature of about 1 ng / ml. The invention relates to a method of administration to the kidney to be maintained below. The present invention is an ambrisentan for use in the pretreatment of the kidney for kidney transplantation, wherein the level of ambrisentan in the vascular clearance of the kidney is maintained below about 1 ng / ml on the treated kidney It relates to the administered ambrisentan. The pretreated kidney can then be transplanted into the subject. The liquid formulation used for pretreatment comprises an effective amount of an endothelin receptor antagonist, preferably ambrisentan. Such an effective amount may be achieved by flushing the kidney with a liquid composition of the invention having an antagonist concentration of 20 to 100 times less than the concentration of the liquid composition used to treat the patient. For example, the kidneys are washed away with 1 liter of a liquid composition containing ambrisentan at a concentration of 0.001 to 1 ng / ml. By pretreating the kidneys to be transplanted with the endothelin receptor antagonist of the present invention, the transplanted kidneys generally function more quickly and are less likely to fail immediately after transplantation, leaving untreated kidneys and the like. It works longer in transplant recipients in comparison. The method may further comprise the step of intravenously administering to the subject a liquid composition of the invention comprising an effective amount of an endothelin receptor antagonist. This further step can further increase the survival rate of the transplanted kidney.

  The invention further relates to the use of the liquid composition of the invention in the preservation of harvested kidneys awaiting transplantation. Thus, the present invention relates to ambrisentan for use in preserving harvested kidneys awaiting transplantation. Furthermore, the present invention provides a method of pre-transplant preservation of kidneys awaiting transplantation by the liquid composition of the present invention, comprising the step of administering to the kidney a liquid composition of the present invention containing an effective amount of endothelin receptor antagonist. Do. Preferably, the present invention further relates to a method of preserving the kidney awaiting transplantation by a liquid composition containing ambrisentan or ambrisentan, wherein an effective amount of ambrisentan is administered to the kidney, in the vascular gap of the kidney The invention relates to methods administered to the kidney such that the level of ambrisentan is maintained below about 1 ng / ml. The invention further relates to an ambrisentan for use in storing kidney suitable for transplantation, wherein the ambrisentan is such that the level of ambrisentan in the vascular space of the kidney is maintained below about 1 ng / ml. Treatment is administered to the kidneys. The liquid formulation used for pretreatment comprises an effective amount of an endothelin receptor antagonist, preferably ambrisentan. By storing the kidneys to be transplanted in a solution containing the endothelin receptor antagonist of the present invention, preferably ambrisentan, the transplanted kidneys generally function more rapidly and may fail immediately after transplantation. It is lower and functions in transplant recipients longer compared to untreated kidneys. The method may further comprise the step of intravenously administering to the subject receiving the kidney a liquid composition of the invention comprising an effective amount of an endothelin receptor antagonist. This further step can further increase the survival rate of the transplanted kidney.

  In a further embodiment, the ambrisentan is at most 1 ng / ml, preferably at most 0.75 ng / ml, more preferably at most 0.5 ng / ml, still more preferably at most 0.4 ng / ml and most preferably many At least 0.2 ng / ml, and generally at least 0.001 ng / ml, preferably at least 0.003 ng / ml, more preferably at least 0.005 ng / ml, even more preferably at least 0.01 ng / ml, and most preferably at least At a concentration of 0.05 ng / ml ambrisentan, it is administered to the kidney or flushed through the kidney to be transplanted.

  The above embodiments also apply to divotentane and atrasentan, including their individual embodiments.

Example 1
Preparation of Ambrisentan solution:
A liquid composition was prepared containing 0.5 mg of ambrisentan per ml of solvent. First, 4.60 g of sodium dihydrogen phosphate monohydrate (NaH ₂ PO ₄ · H ₂ O), 4.73 g of disodium hydrogen phosphate (Na ₂ HPO ₄ ) and 4.80 g of sodium chloride in 1,000 ml of sterile distilled water (qs) And a solution of pH 7.4 was obtained. The resulting solution was heated to 50.degree. Subsequently, 0.50 g of ambrisentan was added and the solution was stirred until the ambrisentan was completely dissolved. The resulting solution was cooled and sterilized by passing the solution through a suitable filter. The resulting liquid composition is according to the invention and contains 0.5 mg / ml of ambrisentan. When the resulting liquid composition was analyzed, the ambrisentan remained stable and no degradation was observed.

Stability Test The liquid composition of Example 1 was tested for its stability. The test was carried out by applying 5 ml of solution in ampoules stored at different temperatures, ie 5 ° C. and 25 ° C., for up to 180 days in conditioned chambers. These solutions showed no chemical and physical degradation of ambrisentan.

Example 2
Preparation of Ambilisentan Formulation:
A liquid composition was prepared containing 10 mg of ambrisentan per 1 ml of solvent. First, 4.00 g of polysorbate 20, 10.00 g of sodium ascorbate, 1.50 g of sodium chloride, 1.10 g of EDTA and 9.20 g of disodium phosphate anhydride are dissolved in 1000 ml of sterile distilled water (qs), pH 8.0 A solution was obtained. The resulting solution was heated to 50 ° C. Subsequently, 10.00 g of ambrisentan was added and the solution was stirred until the ambrisentan was completely dissolved. The resulting solution was cooled and sterilized by passing the solution through a suitable filter. The resulting liquid composition is according to the invention and contains 10 mg / ml of ambrisentan.

Example 3
Treatment of porcine kidney with ambrisentan-containing liquid composition after ischemic injury:
All experiments were performed according to Home Office animals (Scientific Procedures) Act 1986. Ten kidneys were collected from landrace mating sows weighing approximately 50 kg. The two sets of kidneys were subjected to warm ischemic injury for 20 minutes (warm ischaemic injury), then flushed with 500 ml of UW solution at 4 ° C., and stored on ice for 18 hours. After refrigerated storage for 18 hours, the kidneys were prepared and flushed with 100 ml Ringer solution 4 ° C. with or without the liquid composition of Example 1 diluted to an amblysentan concentration of 150 μg / l. They were then left at room temperature for 20 minutes. The remaining 3 sets of kidneys were collected 10 minutes after warm ischemia and stored on ice for 6 hours. They were prepared as described above, flushed and then left at room temperature for 10 minutes prior to reperfusion.

  The kidneys were perfused for 6 hours at 38.0 ° C. with 1 liter of diluted whole autologous heparinized blood to assess renal function and injury. 1000 μmol / l creatinine (Sigma-Aldrich) was added to the circuit. In treated kidneys, the above-mentioned ambrisentan-containing liquid composition (150 μg / l) was added to the reperfusion circuit 10 minutes before the start of reperfusion. Endothelin-1 (Sigma-Aldrich) was added to the arterial system of the reperfusion circuit in control and treated kidneys after 2 hours and 50 minutes of reperfusion to achieve a concentration (20 μg / ml). Samples of perfusate were taken from the kidney vein during flush after storage. Perfusion data were recorded 30 minutes after reperfusion and then hourly. Plasma and urine samples were collected before reperfusion, 30 minutes after reperfusion, and then once an hour to measure kidney function.

Throughout the initial period of renal hemodynamic reperfusion, the levels of renal blood flow and intrarenal resistance were similar between groups. The level of renal blood flow was particularly reduced in the control group 2 hours after reperfusion (Table 1). Renal blood flow in the control group decreased significantly after endothelin administration. Levels also decreased in treated kidneys, but to a lesser extent. After administration of ambrisentan, the intrarenal resistance increased in both groups, and the increase in treated kidney was less pronounced compared to the control group.
Table 1: Renal blood flow and renal resistance

Oxygen Consumption The level of oxygen consumption during reperfusion was measured and is summarized in the following table. The levels between groups one hour after reperfusion were similar. After 3 hours, the level was numerically lower in the control group, and was lower in the control compared to the treated kidney after 6 hours, with significant differences between groups.
Table 2: Oxygen consumption

Urine Output The amount of urine produced was determined in both the subject and the treated kidney. The results are shown in Table 3 below. This table demonstrates that ambrisentan-treated kidneys show higher urine flow.
Table 3: Urine flow rate

Example 4
Preparation of ambrisentan formulation:
A liquid composition was prepared containing 5 mg of ambrisentan per 1 ml of solvent. First, 300 mL of ethanol and 700 mL of propylene glycol 1, 2 were mixed together. The resulting solution was heated to 40.degree. Then 5 g of ambrisentan was added and the solution was stirred until the ambrisentan was completely dissolved. The resulting solution was cooled and sterilized by passing the solution through a suitable filter. The resulting liquid composition is according to the invention and contains 5 mg / mL of ambrisentan. When the resulting liquid composition was analyzed, the ambrisentan remained stable and no degradation was observed.

  The resulting solution can be diluted in various proportions with aqueous saline and other buffers of pH 6 or higher. Prior to human administration, the physician is expected to mix with a sterile aqueous solution to obtain the desired ambrisentan concentration.

Stability Test The stability of the liquid composition of Example 4 was tested. The test was carried out by applying 5 ml of solution in ampoules stored at different temperatures, ie 5 ° C. and 25 ° C., for up to 180 days in conditioned chambers. The solution showed no chemical and physical degradation of ambrisentan at 5 ° C and some degradation was observed at 25 ° C.

Example 5-10
Water-Free Ambrisentan Formulation Various compositions were prepared according to the present invention and Example 4 above using various solvents. To the ambrisentan, the solvent or solvent mixture was added and stirred. An overview of the components of these compositions is given in the following table.
Table 4: Ambrisentan formulation without water

  In addition to the above examples, two-component and three-component solutions can also be prepared for this purpose.

  The invention described herein relates generally to methods and formulations for the treatment and prevention of acute renal failure comprising the administration of an ETR-A antagonist. While specific exemplary embodiments have been described above in detail, it should be understood that such embodiments and examples are merely illustrative of the broad invention and are not limiting. In particular, it should be appreciated that the teachings of the present invention apply to variations of the preferred embodiments specifically discussed. Here, those skilled in the art will recognize modifications, substitutions, changes and equivalents. Accordingly, the present invention is not limited to the specific embodiments or arrangements disclosed, but rather any changes, adaptations or modifications within the scope and spirit of the present invention as defined by the appended claims. Intended to be included.

Example 11
Determine whether low concentrations of ambrisentan in blood treated with ambrisentan in human subjects are unlikely to cause renal side effects as seen at the current concentrations achieved in the current commercial presentation of ambrisentan Did research to In this study, a liquid composition of ambrisentan at a concentration of 5 mg / mL was administered to 20 healthy human subjects at various dosing rates to achieve different ambrisentan concentrations in the blood and for 24 hours . The target concentrations for the low dose group (group A) are 20 and 40 ng / mL at 4 hours and 16 hours respectively, and for the high dose group (group B), 80 and 40 hours after 4 hours and 16 hours It was 160 ng / mL. For groups A and B, first target concentrations of 20 and 80 ng / mL were achieved in 4 hours. For group A and group B, second target concentrations of 40 ng / mL and 160 ng / mL were achieved in 16 hours. The steady state of each target concentration was maintained for at least 8 hours before increasing the concentration. Ten subjects were assigned to group A, and 10 subjects were assigned to group B. Pharmacokinetic and plasma ET-1 samples were collected and analyzed for up to 72 hours at various time points. Urine was collected at intervals of 0-2 hours, 2-4 hours, 4-8 hours, 8-12 hours, 12-18 hours and 18-24 hours for 24 hours.

  All subjects were injected with 100% / hr of 0.45% physiological solution for 24 hours, and ambrisentan was administered over 24 hours with 250 ml of 0.9% physiological solution. The subject was allowed free access to water and regular meals. The subject received at least a total of 2650 mL of water and 223.3 mmol of sodium by intravenous infusion during the 24-hour period of drug administration.

  With regard to the pharmacodynamic effects of ambrisentan, the results show that, at low concentrations, ambrisentan promotes diuresis by increasing urine output, an effect not shown at high concentrations. In fact, concentrations above 100 ng / mL showed significant accumulation of fluid due to the inability to increase urine output. Group A showed higher total urine volume at 24 hours compared to group B, and this difference was already apparent between the start of infusion and the first 4 hours. The effects on urine were consistent throughout the different collection periods of the 24-hour infusion period. Patients in Group A maintained high urine output rates throughout the study compared to Group B. In the table below, the water balance is the result of subtracting the urine volume from the fluid input in the vein.

SEM：平均の標準誤差 Table 5: Water balance by time

SEM: standard error of the mean

SEM：平均の標準誤差 Table 6: Cumulative water balance

SEM: standard error of the mean

  The increase in urinary formation (diuresis) was further characterized by determining the effect of ambrisentan on urinary composition, particularly urinary osmolality. Free Water Clearance (FWC) is the fraction of urine lacking the solute and was higher in Group A than Group B, as determined by the Edelman formula. This further supports the finding that the concentration of ambrisentan achieved in group B tended to inhibit urine formation, while the concentration of ambrisentan achieved in group A promoted urine formation Do. Assuming a significant amount of hypotonic solution was administered intravenously to a subject, as shown in Figure 1, free water clearance was impaired in group B because it remained near or below zero. It was considered.

  Finally, the effect of different concentrations of ambrisentan on ETB receptor blockade was determined by measuring plasma endothelin-1 at different time points in the study. A steady increase of endothelin-1 was observed in the high dose group (Group B) reaching 50% or more from baseline endothelin levels. Less increase in endothelin was observed in group A, but this increase was not considered significant.

  In conclusion, concentrations of total ambrisentan above about 100 ng / mL show deleterious renal effects by promoting fluid retention. Concentrations of total ambrisentan below 100 ng / mL have less effect on fluid retention. Concentrations less than 20 ng / mL have a diuretic effect mainly on free water clearance. Concentrations of total ambrisentan above 100 ng / mL increase plasma endothelin-1 by blockade of ETB receptors.

Claims (56)

  Ambrisentan for use in the treatment of hepatorenal syndrome, wherein ambrisentan is administered to a subject such that plasma levels of ambrisentan are maintained below about 100 ng / ml.   Ambrisentan for use in the treatment of refractory ascites, wherein ambrisentan is administered to a subject such that plasma levels of ambrisentan are maintained below about 100 ng / ml.   Ambrisentan for use in the treatment of dilute hyponatremia, wherein ambrisentan is administered to a subject such that plasma levels of ambrisentan are maintained below about 100 ng / ml.   Ambrisentan for use in the treatment of the calcineurin inhibitor nephrotoxicity, wherein ambrisentan is administered to a subject such that plasma levels of ambrisentan are maintained below about 100 ng / ml.   Ambrisentan is administered to the treated subject such that the plasma level of ambrisentan is maintained below about 100 ng / ml, in the treatment of subjects who may be at risk of developing renal failure associated with solid organ transplantation. Ambrisentan for use.   Ambrisentan for use in the treatment of delayed graft function, wherein Ambrisentan is administered to a subject such that plasma levels of Ambrisentan are maintained below about 100 ng / ml.   Treatment of a subject who is at risk for developing graft function delay after kidney transplantation, wherein ambrisentan is administered to the treatment subject such that plasma level of ambrisentan is maintained below about 100 ng / ml Ambrisentan for use in.   Ambrisentan for use in the treatment of renal failure associated with solid organ transplantation, wherein ambrisentan is administered to a subject such that plasma levels of ambrisentan are maintained below about 100 ng / ml.   Ambrisentan is administered to the treated subject such that the plasma level of ambrisentan is maintained below about 100 ng / ml, in the treatment of subjects who may be at risk of developing renal failure associated with solid organ transplantation. Ambrisentan for use.   Ambrisentan for use in the treatment of cardiorenal syndrome, wherein ambrisentan is administered to a subject such that plasma levels of ambrisentan are maintained below about 100 ng / ml.   Ambrisentan for use in the treatment of acute kidney injury after cardiac surgery, wherein ambrisentan is administered to the subject such that plasma levels of ambrisentan are maintained below about 100 ng / ml.   Use in the treatment of a subject who is at risk for developing acute kidney injury after cardiac surgery, wherein ambrisentan is administered to the treatment subject such that the plasma level of ambrisentan is maintained below about 100 ng / ml Ambrisentan for.   Ambrisentan for use in the treatment of contrast-induced acute kidney injury, wherein ambrisentan is administered to a subject such that plasma levels of ambrisentan are maintained below about 100 ng / ml.   Ambrisentan is administered to the treated subject such that the plasma level of ambrisentan is maintained below about 100 ng / ml, in the treatment of subjects who are at risk of developing contrast agent-induced acute kidney injury Ambrisentan for use.   Ambrisentan for use in the treatment of acute renal failure, wherein ambrisentan is administered to a subject such that plasma levels of ambrisentan are maintained below about 100 ng / ml.   Ambrisentan for use in the treatment of acute renal failure due to vasoconstriction, wherein ambrisentan is administered to a subject such that plasma levels of ambrisentan are maintained below about 100 ng / ml.   Ambrisentan for use in the pretreatment of the kidney for kidney transplantation, administered to the treated kidney such that the level of ambrisentan in the vascular space of the kidney is maintained below about 1 ng / ml.   Ambrisentan for use in the preservation of a kidney suitable for transplantation, administered to the treated kidney such that the level of ambrisentan in the vascular space of the kidney is maintained below about 1 ng / ml.   Ambrisentan is administered to a subject such that plasma levels of ambrisentan are maintained below about 100 ng / ml, for use in treating a subject to identify a decline in renal function due to vasoconstriction Ambrisentan.   Ambrisentan is administered to a treatment subject such that plasma levels of ambrisentan are maintained below about 100 ng / ml, for use in the treatment of a subject suffering from a reduction in renal function due to vasoconstriction. Sentan.   For use in the treatment of a subject suffering from hepatorenal disorder, preferably hepatorenal syndrome, wherein ambrisentan is administered to the subject such that plasma levels of ambrisentan are maintained below about 100 ng / ml , And ambrisentan to identify the decline in renal function due to vasoconstriction.   Ambrisentan is administered to the treated subject such that the plasma level of ambrisentan is maintained below about 100 ng / ml, for use in treating a subject awaiting liver transplantation, and renal function by vasoconstriction Ambrisentan to identify the decline.   Ambrisentan is administered to the treated subject such that the plasma level of ambrisentan is maintained below about 100 ng / ml, waiting for liver transplantation, no improvement in renal function in the subject, double liver- Ambrisentan for use in the treatment of subjects eligible for kidney transplantation, preferably where kidneys are transplanted, and for identifying a reduction in renal function due to vasoconstriction.   Ambrisentan is administered to the treated subject such that the plasma level of ambrisentan is maintained below about 100 ng / ml, for use in treating a subject who has previously undergone renal transplantation, and by vasoconstriction Ambrisentan to identify loss of kidney function.   A method of treating a subject suffering from hepatorenal syndrome, comprising administering an effective amount of ambrisentan to the subject and intravenously administering the ambrisentan or a liquid composition containing ambrisentan, the method comprising: A method wherein Sentan is administered to a subject such that plasma level of Ambrisentan is maintained below about 100 ng / ml.   A method of treating a subject suffering from refractory ascites, comprising administering an effective amount of ambrisentan to the subject and intravenously administering the ambrisentan or a liquid composition containing ambrisentan, A method wherein ambrisentan is administered to a subject such that the plasma level of ambrisentan is maintained below about 100 ng / ml.   A method of treating a subject suffering from dilutable hyponatremia comprising administering an effective amount of ambrisentan to the subject and intravenously administering the ambrisentan or a liquid composition containing ambrisentan A method wherein ambrisentan is administered to a subject such that the plasma level of ambrisentan is maintained below about 100 ng / ml.   A method of treating a subject suffering from a calcineurin inhibitor nephrotoxicity comprising administering to the subject an effective amount of ambrisentan and intravenously administering a liquid composition containing ambrisentan or ambrisentan. A method wherein ambrisentan is administered to a subject such that the plasma level of ambrisentan is maintained below about 100 ng / ml.   There is a possibility that calcineurin inhibitor nephrotoxicity may occur, which comprises administering an effective amount of ambrisentan to a subject and parenterally, preferably intravenously administering a liquid composition containing ambrisentan or ambrisentan A method for prophylactically treating a subject, wherein ambrisentan is administered to a subject such that the plasma level of ambrisentan is maintained below about 100 ng / ml.   A method of treating a subject suffering from delayed graft function comprising administering to the subject an effective amount of ambrisentan and intravenously administering the ambrisentan or a liquid composition comprising ambrisentan. , The method wherein ambrisentan is administered to the subject such that the plasma level of ambrisentan is maintained below about 100 ng / ml.   An effective amount of ambrisentan is administered to a subject, and delayed onset of graft function after kidney transplantation, including parenterally administration, preferably intravenous administration of ambrisentan or a liquid composition containing ambrisentan A method for prophylactically treating a potential subject, wherein ambrisentan is administered to a subject such that the plasma level of ambrisentan is maintained below about 100 ng / ml.   A method of treating a subject suffering from renal failure associated with solid organ transplantation, comprising administering an effective amount of ambrisentan to the subject and intravenously administering the ambrisentan or a liquid composition containing ambrisentan And wherein ambrisentan is administered to the subject such that the plasma level of ambrisentan is maintained below about 100 ng / ml.   An effective amount of ambrisentan can be administered to a subject, and the liquid composition containing ambrisentan or ambrisentan can cause renal failure associated with solid organ transplantation, including parenteral administration, preferably intravenous administration A method for prophylactically treating a subject having sex, wherein ambrisentan is administered to a subject such that plasma level of ambrisentan is maintained below about 100 ng / ml.   A method of treating a subject suffering from cardiorenal syndrome, comprising administering an effective amount of ambrisentan to the subject and intravenously administering the ambrisentan or a liquid composition containing ambrisentan, A method wherein ambrisentan is administered to a subject such that the plasma level of ambrisentan is maintained below about 100 ng / ml.   A method of treating a subject suffering from acute kidney injury after cardiac surgery, comprising administering an effective amount of ambrisentan to the subject and intravenously administering the ambrisentan or a liquid composition containing ambrisentan A method wherein ambrisentan is administered to a subject such that the plasma level of ambrisentan is maintained below about 100 ng / ml.   A subject who may be at risk for developing acute kidney injury after cardiac surgery, including the administration of an effective amount of ambrisentan to the subject and parenteral administration of ambrisentan or a liquid composition containing ambrisentan A method for prophylactically treating, wherein ambrisentan is administered to a subject such that the plasma level of ambrisentan is maintained below about 100 ng / ml.   A method of treating a subject suffering from contrast agent-induced acute kidney injury, comprising administering an effective amount of ambrisentan to a subject and intravenously administering ambrisentan or a liquid composition containing ambrisentan And wherein ambrisentan is administered to the subject such that the plasma level of ambrisentan is maintained below about 100 ng / ml.   A subject who may be at risk of developing contrast agent-induced acute kidney injury, including the administration of an effective amount of ambrisentan to a subject and parenteral administration of ambrisentan or a liquid composition containing ambrisentan A method for prophylactically treating Amblysen, wherein Ambrisentan is administered to a subject such that the plasma level of Ambrisentan is maintained below about 100 ng / ml.   Treating the subject, including: an effective amount of ambrisentan being administered to the subject, renal function being determined before and after treatment, and a liquid composition comprising ambrisentan or ambrisentan being intravenously administered; A method of identifying a reduction in renal function due to contraction, wherein ambrisentan is administered to a subject such that the plasma level of ambrisentan is maintained below about 100 ng / ml.   A method of treating a subject suffering from a reduction in renal function due to vasoconstriction comprising administering an effective amount of ambrisentan to a subject and intravenously administering the ambrisentan or a liquid composition comprising ambrisentan And wherein ambrisentan is administered to the subject such that the plasma level of ambrisentan is maintained below about 100 ng / ml.   A method of treating a subject suffering from acute renal failure comprising administering an effective amount of ambrisentan to the subject and intravenously administering the ambrisentan or a liquid composition containing ambrisentan, A method wherein ambrisentan is administered to a subject such that the plasma level of ambrisentan is maintained below about 100 ng / ml.   A method of treating a subject suffering from acute renal function caused by vasoconstriction, comprising administering an effective amount of ambrisentan to a subject and intravenously administering the ambrisentan or a liquid composition containing ambrisentan A method wherein ambrisentan is administered to a subject such that the plasma level of ambrisentan is maintained below about 100 ng / ml.   Hepatic kidney injury, preferably liver and kidney injury comprising administering an effective amount of ambrisentan to a subject, determining renal function before and after treatment, and intravenously administering the ambrisentan or a liquid composition containing ambrisentan A method of treating a subject suffering from a syndrome and identifying a decrease in renal function due to vasoconstriction such that ambrisentan is treated such that plasma level of ambrisentan is maintained below about 100 ng / ml To be administered to a person.   Subjects awaiting liver transplantation, including effective doses of ambrisentan administered to subjects, renal function determined before and after treatment, and liquid compositions containing ambrisentan or ambrisentan intravenously A method of treating a subject and identifying a decrease in renal function due to vasoconstriction, wherein ambrisentan is administered to a subject such that the plasma level of ambrisentan is maintained below about 100 ng / ml.   An effective amount of ambrisentan is administered to the subject, renal function is determined before and after treatment, and a liquid composition comprising ambrisentan or ambrisentan is intravenously administered, awaiting liver transplantation, A method of treating a subject who is eligible for dual liver-renal transplantation without improvement in renal function in the subject, preferably in which the kidney is transplanted, and for identifying a reduction in renal function due to vasoconstriction, said ambri A method wherein the sentan is administered to the subject such that the plasma level of ambrisentan is maintained below about 100 ng / ml.   An effective amount of ambrisentan is administered to the subject, renal function is determined before and after treatment, and a liquid composition comprising ambrisentan or ambrisentan is intravenously administered, including prior renal transplantation A method of treating a subject and identifying a decrease in renal function due to vasoconstriction, wherein ambrisentan is administered to the subject such that the plasma level of ambrisentan is maintained below about 100 ng / ml. Method.   A method of pre-treating the kidney with ambrisentan or a liquid composition comprising ambrisentan, wherein an effective amount of ambrisentan is administered to the kidney, wherein the level of ambrisentan in the renal vascular space is less than about 1 ng / ml. A method of administering to the kidney to be maintained.   A method for storing a kidney awaiting transplantation by a liquid composition containing ambrisentan or ambrisentan, wherein an effective amount of ambrisentan is administered to the kidney, wherein the level of ambrisentan in the renal vascular gap is about 1 ng / Methods administered to the kidney to be maintained below ml.   A liquid composition for intravenous administration comprising ambrisentan, a buffer and a solvent.   50. The composition of claim 49, wherein the pH of the composition is at least 7.   51. The composition of any one of claims 49 and 50, wherein the liquid composition is free of water.   52. An ampoule comprising a liquid composition according to any one of claims 49 to 51, wherein the ambrisentan is present in a concentration of at least 0.001 wt% and at most 5 wt% based on the total weight of the liquid composition.   52. A pre-filled syringe comprising a liquid composition according to any one of claims 49 to 51, wherein the ambrisentan is present in a concentration of at least 0.001 wt% and at most 1 wt% based on the total weight of the liquid composition. .   52. A subcutaneous pump comprising a liquid composition according to any one of claims 49 to 51, wherein ambrisentan is present in a concentration of at least 0.01 wt% and at most 1 wt% based on the total weight of the liquid composition. Cartridge or hypodermic pump drug reservoir.   52. A subcutaneous pen comprising a liquid composition according to any one of claims 49 to 51, wherein the ambrisentan is present in a concentration of at least 0.01 wt% and at most 1 wt% based on the total weight of the liquid composition. Cartridge.   52. A liquid composition as claimed in any one of claims 49 to 51, wherein the ambrisentan is present in a concentration of at least 0.00001 wt% and at most 0.05 wt% based on the total weight of the liquid composition. container.

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